3, 6-Dihydro-2-Oxo-6H-1,3,4,-Thiadiazine Derivatives

ABSTRACT

Compounds of the formula I, in which R1, R2, Q and B have the meanings indicated in claim  1 , are inhibitors of tyrosine kinases, in particular Met kinase, and can be employed, inter alia, for the treatment of tumours.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to compounds and to the use of compoundsin which the inhibition, regulation and/or modulation of signaltransduction by kinases, in particular tyrosine kinases and/orserine/threonine kinases, plays a role, furthermore to pharmaceuticalcompositions which comprise these compounds, and to the use of thecompounds for the treatment of kinase-induced diseases.

In particular, the present invention relates to compounds and to the useof compounds in which the inhibition, regulation and/or modulation ofsignal transduction by Met kinase plays a role.

One of the principal mechanisms by which cellular regulation is effectedis through the transduction of extracellular signals across the membranethat in turn modulate biochemical pathways within the cell. Proteinphosphorylation represents one course by which intracellular signals arepropagated from molecule to molecule resulting finally in a cellularresponse. These signal transduction cascades are highly regulated andoften overlap, as is evident from the existence of many protein kinasesas well as phosphatases. Phosphorylation of proteins occurspredominantly at serine, threonine or tyrosine residues, and proteinkinases have therefore been classified by their specificity ofphosphorylation site, i.e. serine/threonine kinases and tyrosinekinases. Since phosphorylation is such a ubiquitous process within cellsand since cellular phenotypes are largely influenced by the activity ofthese pathways, it is currently believed that a number of disease statesand/or diseases are attributable to either aberrant activation orfunctional mutations in the molecular components of kinase cascades.Consequently, considerable attention has been devoted to thecharacterisation of these proteins and compounds that are able tomodulate their activity (for a review see: Weinstein-Oppenheimer et al.Pharma. &. Therap., 2000, 88, 229-279).

The role of the receptor tyrosine kinase Met in human oncogenesis andthe possibility of inhibition of HGF (hepatocyte growth factor)dependent Met activation are described by S. Berthou et al. in Oncogene,Vol. 23, No. 31, pages 5387-5393 (2004). The inhibitor SU11274 describedtherein, a pyrrole-indoline compound, is potentially suitable forcombating cancer. Another Met kinase inhibitor for cancer therapy isdescribed by J. G. Christensen et al. in Cancer Res. 2003, 63(21),7345-55.

A further tyrosine kinase inhibitor for combating cancer is reported byH. Hov et al. in Clinical Cancer Research Vol. 10, 6686-6694 (2004). Thecompound PHA-665752, an indole derivative, is directed against the HGFreceptor c-Met. It is furthermore reported therein that HGF and Met makea considerable contribution to the malignant process of various forms ofcancer, such as, for example, multiple myeloma.

The synthesis of small compounds which specifically inhibit, regulateand/or modulate signal transduction by tyrosine kinases and/orserine/threonine kinases, in particular Met kinase, is thereforedesirable and an aim of the present invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

The present invention specifically relates to compounds of the formula Iwhich inhibit, regulate and/or modulate signal transduction by Metkinase, to compositions which comprise these compounds, and to processesfor the use thereof for the treatment of Met kinase-induced diseases andcomplaints, such as angiogenesis, cancer, tumour formation, growth andpropagation, arteriosclerosis, ocular diseases, such as age-inducedmacular degeneration, choroidal neovascularisation and diabeticretinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis,glomerulonephritis, neurodegeneration, psoriasis, restenosis, woundhealing, trans-plant rejection, metabolic diseases and diseases of theimmune system, also autoimmune diseases, cirrhosis, diabetes anddiseases of the blood vessels, also instability and permeability and thelike in mammals.

Solid tumours, in particular fast-growing tumours, can be treated withMet kinase inhibitors. These solid tumours include monocytic leukaemia,brain, urogenital, lymphatic system, stomach, laryngeal and lungcarcinoma, including lung adenocarcinoma and small-cell lung carcinoma.

The present invention is directed to processes for the regulation,modulation or inhibition of Met kinase for the prevention and/ortreatment of diseases in connection with unregulated or disturbed Metkinase activity. In particular, the compounds of the formula I can alsobe employed in the treatment of certain forms of cancer. The compoundsof the formula I can furthermore be used to provide additive orsynergistic effects in certain existing cancer chemotherapies, and/orcan be used to restore the efficacy of certain existing cancerchemotherapies and radiotherapies.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of Met kinase. Inaddition, they are particularly suitable for use in diagnostic methodsfor diseases in connection with unregulated or disturbed Met kinaseactivity.

It can be shown that the compounds according to the invention have anantiproliferative action in vivo in a xenotransplant tumour model. Thecompounds according to the invention are administered to a patienthaving a hyperproliferative disease, for example to inhibit tumourgrowth, to reduce inflammation associated with a lymphoproliferativedisease, to inhibit trans-plant rejection or neurological damage due totissue repair, etc. The pre-sent compounds are suitable for prophylacticor therapeutic purposes. As used herein, the term “treatment” is used torefer to both prevention of diseases and treatment of pre-existingconditions. The prevention of proliferation is achieved byadministration of the compounds according to the invention prior to thedevelopment of overt disease, for example to prevent the growth oftumours, prevent metastatic growth, diminish restenosis associated withcardiovascular surgery, etc. Alternatively, the compounds are used forthe treatment of ongoing diseases by stabilising or improving theclinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a periodine of time whichis sufficient to allow the active agents to induce cell death or toinhibit migration, usually between about one hour and one week. In vitrotesting can be carried out using cultivated cells from a biopsy sample.The viable cells remaining after the treatment are then counted.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compounds according to the invention canalso be used as reagents for testing kinase-dependent signaltransduction pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

For the identification of kinase inhibitors, various assay systems areavailable. In scintillation proximity assay (Sorg et al., J. of.Biomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

Other non-radioactive ELISA assay methods use specificphospho-antibodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J.).

There are many diseases associated with deregulation of cellularproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compounds accordingto the invention are suitable for the treatment of various conditionswhere there is proliferation and/or migration of smooth muscle cellsand/or inflammatory cells into the intimal layer of a vessel, resultingin restricted blood flow through that vessel, for example in the case ofneointimal occlusive lesions. Occlusive graft vascular diseases ofinterest include atherosclerosis, coronary vascular disease aftergrafting, vein graft stenosis, peri-anastomatic prosthetic restenosis,restenosis after angioplasty or stent placement, and the like.

PRIOR ART

Other thiadiazinones are described in WO 03/037349.

4,5-dihydropyrazoles for combating cancer are described in WO 03/079973A2.

Quinoline derivatives are disclosed as Met kinase inhibitors in EP 1 411046 A1.

Pyrrole-indoline derivatives are known as Met kinase inhibitors from WO02/096361 A2.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹ denotes H, A, Hal, OH, OA, SH, SA, SOA, SO₂A, NO₂, NH₂, NHA,    NAA′, SO₂NH₂, SO₂NHA, SO₂NAA′, CONH₂, CONHA, CONAA′, NACOA′,    NASO₂A′, COOH, COOA or CN,-   R² denotes H, A, Hal, SO₂NH₂, SO₂NHA, SO₂NAA′, CONH₂, CONHA, CONAA′,    NACOA′, NASO₂A′, COOH, COOA or CN,-   R¹ and R² together also denote methylenedioxy,-   B is absent, denotes NHCOCONH(CH₂)_(n)R³, NHCOCONA(CH₂)_(n)R³,    NHCOCOO(CH₂)_(n)R³, OCONH(CH₂)_(n)R³, OCONA(CH₂)_(n)R³,    NHCONH(CH₂)_(n)R³, NACONH(CH₂)_(n)R³, N(CH₂)_(n)R³, CONH(CH₂)_(n)R³,    SO₂NH(CH₂)_(n)R³SO₂NA(CH₂)_(n)R³, NHSO₂(CH₂)_(n)R³ or    NASO₂(CH₂)_(n)R³,-   Q is absent or denotes alkylene having 1-4 C atoms,-   R³ denotes R¹, Het or    -   alkyl having 1-6 C atoms or cycloalkyl having 3-8 C atoms, each        of which is unsubstituted or mono-, di-, tri- or        tetrasubstituted by R⁴,-   R⁴ denotes A, Hal, OH, OA, SH, SA, SOA, SO₂A, NO₂, NH₂, NHA, NAA′,    SO₂NH₂, SO₂NHA, SO₂NAA′, CONH₂, CONHA, CONAA′, NACOA′, NASO₂A′,    COOH, COOA or CN,-   Het denotes a mono- or bicyclic saturated heterocycle having 1 to 4    N, O and/or S atoms, which may be unsubstituted or mono-, di- or    trisubstituted by R⁴, CHO, COA, ═S, ═NH, ═NA and/or ═O (carbonyl    oxygen),-   A, A′ each, independently of one another, denote unbranched or    branched alkyl having 1-10 C atoms,    -   in which 1-7H atoms may be replaced by F, Cl and/or Br,        cycloalkyl having 3-8 C atoms or cycloalkylalkylene having 4-10        C atoms,-   Hal denotes F, Cl, Br or I,-   n denotes 0, 1, 2 or 3,    and pharmaceutically usable derivatives, solvates, salts, tautomers    and stereoisomers thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.solvates are, for example, mono- or dihydrates or alkoxides.

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds.

The term prodrug derivatives is taken to mean compounds of the formula Iwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence: improved treatment,healing, prevention or elimination of a disease, syndrome, condition,complaint, disorder or side-effects or also the reduction in the advanceof a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to claims 1-11 and pharmaceutically usable derivatives,salts, solvates and stereoisomers thereof, characterised in that

a) a compound of the formula Ia

in whichB denotes NH₂,and R¹, R² and Q have the meanings indicated in claim 1,is converted into a compound of the formula I in whichB denotes NHCONH(CH₂)_(n)R³,by reacting a compound of the formula Ia with a coupling reagentselected from the group

-   -   a) isoproylidene chloroformate,    -   b) p-nitrophenyl chloroformate,    -   c) diphosgene,    -   d) triphosgene,        and a compound of the formula II

H₂N(CH₂)_(n)R³  II

in which n and R³ have the meanings indicated in claim 1,orb) a compound of the formula Ia is acylated or sulfonylatedand/ora base or acid of the formula I is converted into one of its salts.

Above and below, the radicals R¹, R², Q and B have the meaningsindicated for the formula I, unless expressly stated otherwise.

A or A′ denotes alkyl, is unbranched (linear) or branched, and has 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

Cycloalkylalkylene preferably denotes cyclopropylmethyl,cyclobutylmethyl, cylopentylmethyl, cyclohexylmethyl orcycloheptylmethyl.

Het preferably denotes a monocyclic saturated heterocycle having 1 to 2N and/or O atoms, which may be mono- or disubstituted by A and/or ═O(carbonyl oxygen).

Het particularly preferably denotes piperidinyl, pyrrolidinyl,morpholin-4-yl, piperazinyl, 1,3-oxazolidin-3-yl or imidazolidinyl,where the radicals may also be mono- or disubstituted by A.

R¹ preferably denotes Hal, OH or CN, in particular Cl or OH, veryparticularly preferably 4-Cl.

R² preferably denotes H or Hal, particularly preferably H.

B preferably denotes NHCOCONH(CH₂)_(n)R³, NHCOCOO(CH₂)_(n)R³,NHCONH(CH₂)_(n)R³ or NHSO₂(CH₂)_(n)R³.

The radical B is preferably in the meta-position to Q.

Q preferably denotes CH₂.

R³ preferably denotes H, Het or alkyl having 1-6 C atoms or cycloalkylhaving 3-8 C atoms, each of which is unsubstituted or mono-, di-, tri-or tetrasubstituted by R⁴.

R³ particularly preferably denotes H, 2-hydroxyethyl, 2-hydroxypropyl,pyrrolidinyl, N-methylpyrrolidinyl, morpholin-4-yl,3-(N,N-diethylamino)propyl, 3-(N,N-dimethylamino)propyl, methyl, ethylor propyl.

R⁴ preferably denotes OH, amino, methylamino, dimethylamino, ethylaminoor diethylamino.

Hal preferably denotes F, Cl or Br, but also 1, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ii, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

in Ia R¹ denotes Hal, OH or CN; in Ib R² denotes H or Hal; in Ic Bdenotes NHCOCONH(CH₂)_(n)R³, NHCOCOO(CH₂)_(n)R³, NHCONH(CH₂)_(n)R³ orNHSO₂(CH₂)_(n)R³; in Id Q denotes CH₂; in Ie R³ denotes H, Het or alkylhaving 1-6 C atoms or cycloalkyl having 3-8 C atoms, each of which isunsubstituted or mono-, di-, tri- or tetrasubstituted by R⁴; in If R⁴denotes OH, NH₂, NHA or NAA′; in Ig A, A′ each, independently of oneanother, denote unbranched or branched alkyl having 1-6 C atoms, inwhich 1-5 H atoms may be replaced by F and/or chlorine; in Ih Hetdenotes a monocyclic saturated heterocycle having 1 to 2 N and/or Oatoms, which may be unsubstituted or mono- or disubstituted by A; in IiR¹ denotes Hal, OH or CN, R² denotes H or Hal, B denotesNHCOCONH(CH₂)_(n)R³, NHCOCOO(CH₂)_(n)R³, NHCONH(CH₂)_(n)R³ orNHSO₂(CH₂)_(n)R³, Q denotes CH₂, R³ denotes H, Het or alkyl having 1-6 Catoms or cycloalkyl having 3-8 C atoms, each of which is unsubstitutedor mono-, di-, tri- or tetrasubstituted by R⁴, R⁴ denotes OH, NH₂, NHAor NAA′, A, A′ each, independently of one another, denote unbranched orbranched alkyl having 1-6 C atoms, in which 1-5 H atoms may be replacedby F and/or chlorine, Het denotes a monocyclic saturated heterocyclehaving 1 to 2 N and/or O atoms, which may be unsubstituted or mono- ordisubstituted by A, Hal denotes F, Cl, Br or I, n denotes 0, 1, 2 or 3;and pharmaceutically usable derivatives, salts, solvates, tautomers andstereoisomers thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The starting compounds of the formulae Ia and Il are generally known. Ifthey are novel, however, they can be prepared by methods known per se.

Compounds of the formula I in which B denotes NHCONH(CH₂)_(n)R³ canpreferably be obtained by reacting a compound of the formula Ia with acoupling reagent selected from the group

-   -   a) isoproylidene chloroformate,    -   b) p-nitrophenyl chloroformate,    -   c) diphosgene,    -   d) triphosgene,        and a compound of the formula II. The reaction is preferably        carried out as a one-pot reaction.

The reaction is generally carried out in an inert solvent.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −15° and150°, normally between −5° and 90°, particularly preferably between 20°and 60° C.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to THF, dichloromethane and/or DMF.

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline-earth metal hydroxide, carbonateor bicarbonate or of another salt of a weak acid of the alkali oralkaline-earth metals, preferably of potassium, sodium, calcium orcaesium, may also be favourable.

Compounds of the formula I in which B denotes NHCOCONH(CH₂)_(n)R³ orNHCOCOO(CH₂)_(n)R³ can preferably be obtained by reacting a compound ofthe formula Ia with an alkyl chloroformyl formate, subsequentlyhydrolysing the alkyl oxalaminate, and reacting the resultant oxalamicacid with a compound of the formula II.

An activated ester is advantageously formed in situ here, for examplethrough addition of HOBt (hydroxybenzotriazole) or N-hydroxysuccinimide.Radicals of this type for activation of the carboxyl group in typicalacylation reactions are described in the literature (for example in thestandard works, such as Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart;).

The reaction is carried out in the presence of a carbodiimide, such as,for example, EDCl (N-ethyl-N,N′-(dimethylaminopropyl)carbodiimide) ordicyclohexylcarbodiimide, an organic base, such as, for example,N-methylmorpholine, and in an inert solvent as indicated above.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −15° and150°, normally between −5° and 90°, particularly preferably between 20°and 60° C.

Compounds of the formula I can furthermore be obtained by acylating orsulfonylating compounds of the formula Ia. This is carried out understandard conditions.

The reaction is generally carried out in an inert solvent.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −15° and150°, normally between −5° and 90°, particularly preferably between 20°and 60° C.

Suitable inert solvents are those mentioned above.

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline-earth metal hydroxide, carbonateor bicarbonate or of another salt of a weak acid of the alkali oralkaline-earth metals, preferably of potassium, sodium, calcium orcaesium, may also be favourable.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline-earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline-earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline-earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner.

The free acid forms differ in a certain respect from the correspondingsalt forms thereof with respect to certain physical properties, such assolubility in polar solvents; for the purposes of the invention,however, the salts otherwise correspond to the respective free acidforms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol.

A flavour, preservative, dispersant and dye may likewise be present.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts, solvates and physiologicallyfunctional derivatives thereof can also be administered in the form ofliposome delivery systems, such as, for example, small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from various phospholipids, such as, forexample, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions pre-pared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment of tyrosinekinase-induced diseases. These diseases include the proliferation oftumour cells, pathological neovascularisation (or angiogenesis) whichpromotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts and solvates thereoffor the preparation of a medicament for the treatment or prevention ofcancer. Preferred carcinomas for the treatment originate from the groupcerebral carcinoma, urogenital tract carcinoma, carcinoma of thelymphatic system, stomach carcinoma, laryngeal carcinoma and lungcarcinoma. A further group of preferred forms of cancer are monocyticleukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreaticcancer, glioblastomas and breast carcinoma.

Also encompassed is the use of the compounds according to claim 1according to the invention and/or physiologically acceptable salts andsolvates thereof for the preparation of a medicament for the treatmentor prevention of a disease in which angiogenesis is implicated.

Such a disease in which angiogenesis is implicated is an ocular disease,such as retinal vascularisation, diabetic retinopathy, age-inducedmacular degeneration and the like.

The use of compounds of the formula I and/or physiologically acceptablesalts and solvates thereof for the preparation of a medicament for thetreatment or prevention of inflammatory diseases also falls within thescope of the present invention. Examples of such inflammatory diseasesinclude rheumatoid arthritis, psoriasis, contact dermatitis, delayedhypersensitivity reaction and the like.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of atyrosine kinase-induced disease or a tyrosine kinase-induced conditionin a mammal, in which to this method a therapeutically effective amountof a compound according to the invention is administered to a sickmammal in need of such treatment. The therapeutic amount variesaccording to the specific disease and can be determined by the personskilled in the art without undue effort.

The present invention also encompasses the use compounds of the formulaI and/or physiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of retinalvascularisation.

Methods for the treatment or prevention of ocular diseases, such asdiabetic retinopathy and age-induced macular degeneration, are likewisepart of the invention. The use for the treatment or prevention ofinflammatory diseases, such as rheumatoid arthritis, psoriasis, contactdermatitis and delayed hypersensitivity reaction, as well as thetreatment or prevention of bone pathologies from the group osteosarcoma,osteoarthritis and rickets, likewise falls within the scope of thepresent invention.

The expression “tyrosine kinase-induced diseases or conditions” refersto pathological conditions that depend on the activity of one or moretyrosine kinases. Tyrosine kinases either directly or indirectlyparticipate in the signal transduction pathways of a variety of cellularactivities, including proliferation, adhesion and migration anddifferentiation. Diseases associated with tyrosine kinase activityinclude proliferation of tumour cells, pathological neovascularisationthat promotes the growth of solid tumours, ocular neovascularisation(diabetic retinopathy, age-induced macular degeneration and the like)and inflammation (psoriasis, rheumatoid arthritis and the like).

The compounds of the formula I can be administered to patients for thetreatment of cancer, in particular fast-growing tumours.

The invention thus relates to the use of compounds of the formula I, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, for the preparation of amedicament for the treatment of diseases in which the inhibition,regulation and/or modulation of kinase signal transduction plays a role.

Preference is given here to Met kinase.

Preference is given to the use of compounds of the formula I, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios,

for the preparation of a medicament for the treatment of diseases whichare influenced by inhibition of tyrosine kinases by the compoundsaccording to claim 1.

Particular preference is given to the use for the preparation of amedicament for the treatment of diseases which are influenced byinhibition of Met kinase by the compounds according to claim 1.

Especial preference is given to the use for the treatment of a diseasewhere the disease is a solid tumour.

The solid tumour is preferably selected from the group of tumours of thelung, squamous epithelium, the bladder, the stomach, the kidneys, ofhead and neck, the oesophagus, the cervix, the thyroid, the intestine,the liver, the brain, the prostate, the urogenital tract, the lymphaticsystem, the stomach and/or the larynx.

The solid tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myeloid leukaemia, chronic myeloidleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:

(i) antiproliferative/antineoplastic/DNA-damaging agents andcombinations thereof, as used in medical oncology, such as alkylatingagents (for example cis-platin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chloroambucil, busulphan and nitrosoureas);antimetabolites (for example antifolates such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosinearabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (forexample anthracyclines, such as adriamycin, bleomycin, doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin andmithramycin); antimitotic agents (for example vinca alkaloids, likevincristine, vinblastine, vindesine and vinorelbine, and taxoids, liketaxol and taxotere); topoisomerase inhibitors (for exampleepipodophyllotoxins, like etoposide and teniposide, amsacrine,topotecan, irinotecan and camptothecin) and cell-differentiating agents(for example all-trans-retinoic acid, 13-cis-retinoic acid andfenretinide);(ii) cytostatic agents, such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordownregulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progesterones (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase, such as finasteride;(iii) agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors, like marimastat, and inhibitors ofurokinase plasminogen activator receptor function);(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors, such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;(v) antiangiogenic agents, such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in published international patentapplications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) andcompounds that work by other mechanisms (for example linomide,inhibitors of integrin αvβ3 function and angiostatin);(vi) vessel-damaging agents, such as combretastatin A4 and compoundsdisclosed in international patent applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-Ras antisense;(viii) gene therapy approaches, including, for example, approaches forreplacement of aberrant genes, such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme, and approaches for increasing patient toleranceto chemotherapy or radiotherapy, such as multi-drug resistance genetherapy; and(ix) immunotherapy approaches, including, for example, ex-vivo andin-vivo approaches for increasing the immunogenicity of patient tumourcells, such as transfection with cytokines, such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches for decreasing T-cell anergy, approaches using transfectedimmune cells, such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines, and approaches usinganti-idiotypic antibodies.

The medicaments from Table 1 below are preferably, but not exclusively,combined with the compounds of the formula I.

TABLE 1 alkylating agents cyclophosphamide Lomustine BusulfanProcarbazine Ifosfamide Altretamine Melphalan Estramustine phosphateHexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucilTemozolomide Dacarbazine Semustine Carmustine platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson TetraplatinMatthey) Ormiplatin BBR-3464 Iproplatin (Hoffrnann-La Roche) SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-fluorouracilFludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Idatrexate Roche)Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicin Exatecan mesylate Etoposide (Daiichi) Teniposideor Quinamed (ChemGenex) mitoxantrone Gimatecan (Sigma-Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour- 7-Ethyl-10- Ipsen) hydroxycamptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet J-107088(Merck & Co) (TopoTarget) BNP-1350 (BioNumerik) Pixantrone(Novuspharrna) CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour Dactinomycin(Actinomycin Amonafide antibiotics D) Azonafide Doxorubicin (Adriamycin)Anthrapyrazole Deoxyrubicin Oxantrazole Valrubicin LosoxantroneDaunorubicin Bleomycin sulfate (Daunomycin) (Blenoxan) EpirubicinBleomycinic acid Therarubicin Bleomycin A Idarubicin Bleomycin BRubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) PorfiromycinGPX-100 (Gem Cyanomorpholinodoxorubicin Pharmaceuticals) Mitoxantron(Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel(GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL (CellVincristine Therapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A105972 (Abbott) Dolastatin 10 (NCl) A 204197 (Abbott) Rhizoxin(Fujisawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica)Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar)Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik)PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB (PrescientAuristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-Prodrug(OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga)CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestan inhibitorsLetrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi)Formestan Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias)synthase ZD-9331 (BTG) CoFactor ™ (BioKeys) inhibitors DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-Benzylguanine Thymectacin(NewBiotics) (Paligent) Edotreotid (Novartis) Farnesyl Arglabin(NuOncology Tipifarnib (Johnson & transferase Labs) Johnson) inhibitorsIonafarnib (Schering- Perillyl alcohol (DOR Plough) BioPharma)BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) ZosuquidarTariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate transferase inhibitors SAHA (Aton Pharma)(Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa) MetalloproteinaseNeovastat (Aeterna Laboratories) CMT-3 (CollaGenex) inhibitorsMarimastat (British Biotech) BMS-275291 (Celltech) RibonucleosideGallium maltolate (Titan) Tezacitabine (Aventis) reductase inhibitorsTriapin (Vion) Didox (Molecules for Health) TNF-alpha Virulizin (LorusTherapeutics) Revimid (Celgene) agonists/ CDC-394 (Celgene) antagonistsEndothelin-A receptor Atrasentan (Abbot) YM-598 (Yamanouchi) antagonistsZD-4054 (AstraZeneca) Retinoic acid receptor Fenretinide (Johnson &Alitretinoin (Ligand) agonists Johnson) LGD-1550 (Ligand)Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology)Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccines (CTL !3-Alethin (Dovetail) Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (Gem- Vax) Hormonal and OestrogensPrednisone antihormonal Conjugated oestrogens Methylprednisolone agentsEthynyloestradiol Prednisolone chlorotrianisene AminoglutethimideIdenestrol Leuprolide Hydroxyprogesterone Goserelin caproate LeuporelinMedroxyprogesterone Bicalutamide Testosterone Flutamide Testosteronepropionate Octreotide Fluoxymesterone Nilutamide MethyltestosteroneMitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyoestradiol(Entre Tamoxifen Med) Toremofin Arzoxifen (Eli Lilly) DexamethasonePhotodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbid agentsTheralux (Theratechnologies) (Yeda) Motexafin-GadoliniumLutetium-Texaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosinekinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitorsLeflunomide(Sugen/Pharmacia) CEP-701 (Cephalon) ZDI839 (AstraZeneca)CEP-751 (Cephalon) Erlotinib (Oncogene Science) MLN518 (Millenium)Canertjnib (Pfizer) PKC412 (Novartis) Squalamine (Genaera) Phenoxodiol OSU5416 (Pharmacia) Trastuzumab (Genentech) SU6668 (Pharmacia) C225(ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca)MDX-H210 (Medarex) Vatalanib (Novartis) 2C4 (Genentech) PKI166(Novartis) MDX-447 (Medarex) GW2016 (GlaxoSmith- ABX-EGF (Abgenix)Kline) IMC-1C11 (ImClone) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo)BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist,Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin(RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor,Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2inhibitor, N-Acetylcysteine (reducing Phytopharm) agent, Zambon)CapCell ™ (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic)inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaBGlycoGenesys) inhibitor, Active Biotech) G17DT immunogen (gastrinSeocalcitol (vitamin D inhibitor, Aphton) receptor agonist, Leo)Efaproxiral (oxygenator, 131-I-TM-601 (DNA Allos Therapeutics)antagonist, PI-88 (heparanase inhibitor, TransMolecular) Progen)Eflornithin (ODC inhibitor, Tesmilifen (histamine antagonist, ILEXOncology) YM BioSciences) Minodronic acid Histamine (histamine H2(osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin(IMPDH inhibitor, Indisulam (p53 stimulant, Ribapharm) Eisai)Cilengitide (integrin antagonist, Aplidin (PPT inhibitor, Merck KGaA)PharmaMar) SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody,Sanofi-Synthelabo) Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33inhibitor, Wyeth) antibody, Wyeth Ayerst) Exisulind (PDE-V inhibitor,PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461(PDE-V inhibitor, Immunol ™ (triclosan Cell Pathways) mouthwash, Endo)AG-2037 (GART inhibitor, Triacetyluridine (uridine Pfizer) prodrug,Wellstat) WX-UK1 (plasminogen SN-4071 (sarcoma agent, activatorinhibitor, Wilex) Signature BioScience) PBI-1402 (PMN stimulant,TransMID-107 ™ ProMetic LifeSciences) (immunotoxin, KS Bortezomib(proteasome Biomedix) inhibitor, Millennium) PCK-3145 (apoptosis SRL-172(T-cell stimulant, promoter, Procyon) SR Pharma) Doranidazole (apoptosisTLK-286 (glutathione-S promoter, Pola) transferase inhibitor, Telik)CHS-828 (cytotoxic agent, PT-100 (growth factor Leo) agonist, PointTherapeutics) Trans-retinic acid Midostaurin (PKC inhibitor,(differentiator, NIH) Novartis) MX6 (apoptosis promoter, Bryostatin-1(PKC stimulant, MAXIA) GPC Biotech) Apomine (apoptosis CDA-II (apoptosispromoter, promoter, ILEX Oncology) Everlife) Urocidin (apoptosis SDX-101(apoptosis promoter, promoter, Bioniche) Salmedix) Ro-31-7453 (apoptosisCeflatonin (apoptosis promoter, promoter, La Roche) ChemGenex)Brostallicin (apoptosis promoter, Pharmacia) alkylating agentscyclophosphamide Lomustine Busulfan Procarbazine Ifosfamide AltretamineMelphalan Estramustine phosphate Hexamethylmelamine MechloroethamineThiotepa Streptozocin chloroambucil Temozolomide Dacarbazine SemustineCarmustine Platinum agents Cisplatin Carboplatin Oxaliplatin ZD-0473(AnorMED) Spiroplatin Lobaplatin (Aetema) CarboxyphthalatoplatinumSatraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 Iproplatin(Hoffrnann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access)Antimetabolites Azacytidine Tomudex Gemcitabine TrimetrexateCapecitabine Deoxycoformycin 5-fluorouracil Fludarabine FloxuridinePentostatin 2-chlorodesoxyadenosine Raltitrexed 6-MercaptopurineHydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine(Bioenvision) 2-fluorodesoxycytidine Irofulven (MGI Pharrna)Methotrexate DMDC (Hoffmann-La Idatrexate Roche) Ethynylcytidine (Taiho)Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors EpirubicinExatecan mesylate Etoposide (Daiichi) Teniposide or Quinamed (ChemGenex)mitoxantrone Gimatecan (Sigma-Tau) Irinotecan (CPT-11) Diflomotecan(Beaufour- 7-Ethyl-10- Ipsen) hydroxycamptothecin TAS-103 (Taiho)Topotecan Elsamitrucin (Spectrum) Dexrazoxanet J-107088 (Merck & Co)(TopoTarget) BNP-1350 (BioNumerik) Pixantrone (Novuspharrna) CKD-602(Chong Kun Rebeccamycin analogue Dang) (Exelixis) KW-2170 (Kyowa Hakko)BBR-3576 (Novuspharrna) Antitumour Dactinomycin (Actinomycin Amonafideantibiotics D) Azonafide Doxorubicin (Adriamycin) AnthrapyrazoleDeoxyrubicin Oxantrazole Valrubicin Losoxantrone Daunorubicin Bleomycinsulfate (Daunomycin) (Blenoxan) Epirubicin Bleomycinic acid TherarubicinBleomycin A Idarubicin Bleomycin B Rubidazon Mitomycin C PlicamycinpMEN-10755 (Menarini) Porfiromycin GPX-100 (GemCyanomorpholinodoxorubicin Pharmaceuticals) Mitoxantron (Novantron)Antimitotic agents Paclitaxel SB 408075 Docetaxel (GlaxoSmithKline)Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cell VincristineTherapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A 105972 (Abbott)Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 223651(BASF) Mivobulin (Warner- D 24851 (ASTA Medica) Lambert) ER-86526(Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis)Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilone B(Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel(Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly)!DN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient Auristatin PE(Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS 247550 (BMS)BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-Prodrug (OXiGENE) BMS 188797(BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE) AromataseAminoglutethimide Exemestan inhibitors Letrozole Atamestan(BioMedicines) Anastrazole YM-511 (Yamanouchi) Formestan ThymidylatePemetrexed (Eli Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG)CoFactor ™ (BioKeys) inhibitors DNA antagonists Trabectedin (PharmaMar)Mafosfamide (Baxter Glufosfamide (Baxter International) International)Apaziquone (Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions)O6-Benzylguanine Thymectacin (NewBiotics) (Paligent) Edotreotid(Novartis) Farnesyl Arglabin (NuOncology Tipifarnib (Johnson &transferase Labs) Johnson) inhibitors Ionafarnib (Schering- Perillylalcohol (DOR Plough) BioPharma) BAY-43-9006 (Bayer) Pump inhibitorsCBT-1 (CBA Pharma) Zosuquidar Tariquidar (Xenova) trihydrochloride (EliLilly) MS-209 (Schering AG) Biricodar dicitrate (Vertex) Histone acetylTacedinaline (Pfizer) Pivaloyloxymethyl butyrate transferase SAHA (AtonPharma) (Titan) inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna CMT-3 (CollaGenex) inhibitorsLaboratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (BritishTezacitabine (Aventis) reductase Biotech) Didox (Molecules forinhibitors Gallium maltolate (Titan) Health) Triapin (Vion) TNF-alphaVirulizin (Lorus Revimid (Celgene) agonists/ Therapeutics) antagonistsCDC-394 (Celgene) Endothelin-A Atrasentan (Abbot) YM-598 (Yamanouchi)receptor ZD-4054 (AstraZeneca) antagonists Retinoic acid Fenretinide(Johnson & Alitretinoin (Ligand) receptor agonists Johnson) LGD-1550(Ligand) Immuno- Interferon Dexosome therapy modulators Oncophage(Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian CancerAdenocarcinoma vaccine Technology) (Biomira) JSF-154 (Tragen) CTP-37(AVI BioPharma) Cancer vaccine (Intercell) JRX-2 (Immuno-Rx) Norelin(Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Synchrovax vaccines(CTL MGV (Progenics) Immuno) !3-Alethin (Dovetail) Melanoma vaccine (CTLCLL-Thera (Vasogen) Immuno) p21-RAS vaccine (GemVax) Hormonal andOestrogens Prednisone antihormonal Conjugated oestrogensMethylprednisolone agents Ethynyloestradiol Prednisolonechlorotrianisene Aminoglutethimide Idenestrol LeuprolideHydroxyprogesterone Goserelin caproate Leuporelin MedroxyprogesteroneBicalutamide Testosterone Flutamide Testosterone propionate OctreotideFluoxymesterone Nilutamide Methyltestosterone Mitotan DiethylstilbestrolP-04 (Novogen) Megestrol 2-Methoxyoestradiol Tamoxifen (EntreMed)Toremofin Arzoxifen (Eli Lilly) Dexamethasone Photodynamic Talaporfin(Light Sciences) Pd-Bacteriopheophorbid agents Theralux (Yeda)(Theratechnologies) Lutetium-Texaphyrin Motexafin-Gadolinium(Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib(Novartis) Kahalide F (PharmaMar) inhibitorsLeflunomide(Sugen/Pharmacia) CEP-701 (Cephalon) ZDI839 (AstraZeneca)CEP-751 (Cephalon) Erlotinib (Oncogene MLN518 (Millenium) Science)PKC412 (Novartis) Canertjnib (Pfizer) Phenoxodiol O Squalamine (Genaera)Trastuzumab (Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668(Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex)ZD6474 (AstraZeneca) 2C4 (Genentech) Vatalanib (Novartis) MDX-447(Medarex) PKI166 (Novartis) ABX-EGF (Abgenix) GW2016 IMC-1C11 (ImClone)(GlaxoSmithKline) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A BCX-1777 (PNP inhibitor, inhibitor, Sanofi- BioCryst)Synthelabo) Ranpirnase (ribonuclease Tocladesine (cyclic AMP stimulant,Alfacell) agonist, Ribapharm) Galarubicin (RNA Alvocidib (CDK inhibitor,synthesis inhibitor, Dong- Aventis) A) CV-247 (COX-2 inhibitor,Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2inhibitor, N-Acetylcysteine (reducing Phytopharm) agent, Zambon)CapCell ™ (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic)inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaBGlycoGenesys) inhibitor, Active Biotech) G17DT immunogen Seocalcitol(vitamin D (gastrin inhibitor, Aphton) receptor agonist, Leo)Efaproxiral (oxygenator, 131-I-TM-601 (DNA Allos Therapeutics)antagonist, PI-88 (heparanase TransMolecular) inhibitor, Progen)Eflornithin (ODC inhibitor, Tesmilifen (histamine ILEX Oncology)antagonist, YM Minodronic acid BioSciences) (osteoclast inhibitor,Histamine (histamine H2 Yamanouchi) receptor agonist, Maxim) Indisulam(p53 stimulant, Tiazofurin (IMPDH Eisai) inhibitor, Ribapharm) Aplidin(PPT inhibitor, Cilengitide (integrin PharmaMar) antagonist, Merck KGaA)Rituximab (CD20 antibody, SR-31747 (IL-1 antagonist, Genentech)Sanofi-Synthelabo) Gemtuzumab (CD33 CCI-779 (mTOR kinase antibody, WyethAyerst) inhibitor, Wyeth) PG2 (haematopoiesis Exisulind (PDE-Vinhibitor, promoter, Pharmagenesis) Cell Pathways) Immunol ™ (triclosanCP-461 (PDE-V inhibitor, mouthwash, Endo) Cell Pathways)Triacetyluridine (uridine AG-2037 (GART inhibitor, prodrug, Wellstat)Pfizer) SN-4071 (sarcoma agent, WX-UK1 (plasminogen SignatureBioScience) activator inhibitor, Wilex) TransMID-107 ™ PBI-1402 (PMNstimulant, (immunotoxin, KS ProMetic LifeSciences) Biomedix) Bortezomib(proteasome PCK-3145 (apoptosis inhibitor, Millennium) promoter,Procyon) SRL-172 (T-cell stimulant, Doranidazole (apoptosis SR Pharma)promoter, Pola) TLK-286 (glutathione-S CHS-828 (cytotoxic agent,transferase inhibitor, Telik) Leo) PT-100 (growth factor Trans-retinicacid agonist, Point (differentiator, NIH) Therapeutics) MX6 (apoptosispromoter, Midostaurin (PKC inhibitor, MAXIA) Novartis) Apomine(apoptosis Bryostatin-1 (PKC promoter, ILEX Oncology) stimulant, GPCBiotech) Urocidin (apoptosis CDA-II (apoptosis promoter, Bioniche)promoter, Everlife) Ro-31-7453 (apoptosis SDX-101 (apoptosis promoter,La Roche) promoter, Salmedix) Brostallicin (apoptosis Ceflatonin(apoptosis promoter, Pharmacia) promoter, ChemGenex)

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

Assays

The compounds of the formula I described in the examples were tested bythe assays described below and were found to have kinase inhibitoryactivity. Other assays are known from the literature and could readilybe performed by the person skilled in the art (see, for example,Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem.274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk etal., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst.52:413-427; Nicosia et al., In Vitro 18:538-549).

Measurement of Met Kinase Activity

According to the manufacturer's data (Met, active, upstate, catalogueNo. 14-526), Met kinase is expressed for the purposes of proteinproduction in insect cells (Sf21; S. frugiperda) and subsequentaffinity-chromatographic purification as “N-terminal 6His-tagged”recombinant human protein in a baculovirus expression vector.

The kinase activity can be measured using various available measurementsystems. In the scintillation proximity method (Sorg et al., J. ofBiomolecular Screening, 2002, 7, 11-19), the flashplate method or thefilter binding test, the radioactive phosphorylation of a protein orpeptide as substrate is measured using radioactively labelled ATP(³²P-ATP, ³³P-ATP). In the case of the presence of an inhibitorycompound, a reduced radioactive signal, or none at all, can be detected.Furthermore, homogeneous time-resolved fluorescence resonance energytransfer (HTR-FRET) and fluoroescence polarisation (FP) technologies canbe used as assay methods (Sills et al., J. of Biomolecular Screening,2002, 191-214).

Other non-radioactive ELISA assay methods use specificphospho-anti-bodies (phospho-ABs). The phospho-antibody only binds thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated antibody (Ross etal., 2002, Biochem. J.).

Flashplate Method (Met Kinase)

The test plates used are 96-well Flashplate® microtitre plates fromPerkin Elmer (Cat. No. SMP200). The components of the kinase reactiondescribed below are pipetted into the assay plate. The Met kinase andthe substrate poly Ala-Glu-Lys-Tyr, (pAGLT, 6:2:5:1), are incubated for3 hrs at room temperature with radioactively labelled ³³P-ATP in thepresence and absence of test substances in a total volume of 100 μl. Thereaction is terminated using 150 μl of a 60 mM EDTA solution. Afterincubation for a further 30 min at room temperature, the supernatantsare filtered off with suction, and the wells are washed three times with200 μl of 0.9% NaCl solution each time. The measurement of the boundradioactivity is carried out by means of a scintillation measuringinstrument (Topcount NXT, Perkin-Elmer).

The full value used is the inhibitor-free kinase reaction. This shouldbe approximately in the range 6000-9000 cpm. The pharmacological zerovalue used is staurosporin in a final concentration of 0.1 mM. Theinhibitory values (IC50) are determined using the RS1_MTS program.

Kinase Reaction Conditions per Well:

30 μl of assay buffer10 μl of substance to be tested in assay buffer with 10% of DMSO10 μl of ATP (final concentration 1 μM cold, 0.35 μCi of ³³P-ATP)50 μl of Met kinase/substrate mixture in assay buffer;

-   -   (10 ng of enzyme/well, 50 ng of pAGLT/well)

Solutions Used:

-   -   Assay Buffer:    -   50 mM HEPES    -   3 mM magnesium chloride    -   3 μM sodium orthovanadate    -   3 mM manganese(II) chloride    -   1 mM dithiothreitol (DTT)    -   pH=7.5 (to be set using sodium hydroxide)

Stop Solution:

-   -   60 mM Titriplex III (EDTA)    -   ³³P-ATP: Perkin-Elmer;    -   Met kinase: Upstate, Cat. No. 14-526, Stock 1 μg/10 μl; spec.        activity 954 U/mg;    -   Poly-Ala-Glu-Lys-Tyr, 6:2:5:1:Sigma Cat. No. P1152

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the residue is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺        APCI-MS (atmospheric pressure chemical ionisation—mass        spectrometry) (M+H)⁺.

Retention Time RT [Min]: Determination by HPLC Column:ChromolithPerformance RP-18e (Merck KGaA, Cat. 1.02129.0001) Eluents:

Eluent A: 0.1 M aqueous NaH₂PO₄Eluent B: acetonitrile+10% of waterFlow rate: 4 ml/min

Gradient: 0 min 1% of B 1 min 1% of B 7 min 99% of B 8 min 99% of B

Wavelength (detection): 220 nm

EXAMPLE 1

The preparation of1-{3-[5-(4-chlorophenyl)-2-oxo-6H-1,3,4-thiadiazin-3-ylmethyl]phenyl}-3-(1-methylpyrrolidin-3-ylmethyl)urea(“A1”) is carried out analogously to the following scheme

a)

If the requisite haloacetophenones are not commercially available, theycan be prepared analogously to the following synthetic procedure:

5.57 g of 3,4-dimethoxyacetophenone are dissolved in 60 ml of diethylether and 30 ml of 1,4-dioxane in a 250 ml three-necked flask providedwith magnetic stirrer, condenser, thermometer, dropping funnel withpressure equalisation and drying tube, and 1.54 ml of bromine are addeddropwise with stirring at RT, during which a precipitate forms afteronly a short time. The mixture is stirred at RT for a further 1 h,during which the precipitate re-dissolves, the temperature is raised byabout 3° C., and a pale-yellow, clear solution forms. This is pouredonto ice, stirred well, and the precipitate formed between the phases isfiltered off with suction. It is washed with water and then with alittle MTB ether and dried (=K1). The mother liquor is extracted withMTB ether, dried, filtered and evaporated to dryness. The residue istriturated with a little MTB ether, filtered off with suction and dried(=K2). K1 and K2 are combined, giving 2′-bromo-4-chloroacetophenone,m.p. 91-92°; yield: 5.88 g (76%).

b)

8.09 ml of hydrazinium hydroxide are slowly added dropwise to a solutionof 25.65 g of potassium O-ethyldithiocarbonate in 24 ml of water withstirring, and the mixture is stirred at room temperature for a further 6h. The mixture is left to stand at room temperature for 16 h, then 12 mlof water are added, and the mixture is extracted with ether. Thecombined ether phases are dried, filtered and evaporated to dryness,giving 16.4 g of ethyl hydrazinecarbothionate.

c)

5.17 g of ethyl hydrazinecarbothionate (43 mmol) are added to a solutionof 10.04 g of 2′-bromo-4-chloroacetophenone (43 mmol) in 40 ml ofacetonitrile, and the mixture is stirred at RT for 3 h, during which aprecipitate forms little by little. The reaction mixture is filteredwith suction, washed with a little acetonitrile and then with ether anddried, giving 6.59 g (68%) of5-(4-chlorophenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one.

d)

4.19 g of 3-nitrobenzyl bromide and 9.95 g of potassium carbonate areadded to a solution of 4.00 g of5-(4-chlorophenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one in 80 ml ofacetonitrile, and the mixture is stirred at 80° for a further 2 h. Themixture is poured into water, extracted 2× with diethyl ether, dried,filtered and evaporated to dryness. A little diethyl ether is added tothe residue, which is crystallised and dried in a vacuum drying cabinetat 50° C., giving 5.5 g (86%) of5-(4-chlorophenyl)-3-(3-nitrobenzyl)-3,6-dihydro-1,3,4-thiadiazin-2-one.

e)

5.47 g of5-(4-chlorophenyl)-3-(3-nitrobenzyl)-3,6-dihydro-1,3,4-thiadiazin-2-oneis dissolved in 100 ml of THF, and 1.3 g of Raney nickel is subsequentlyadded. Hydrogen is subsequently passed in until starting material is nolonger detectable. For work-up, the catalyst is filtered off, washedwith THF, and the filtrate is evaporated to dryness and recrystallisedfrom dichloromethane/diethyl ether, giving 4.6 g (94%) of3-(3-aminobenzyl)-5-(4-chlorophenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one.

f)

200 mg (0.603 mmol) of3-(3-aminobenzyl)-5-(4-chlorophenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one,121 mg (0.603 mmol) of 4-nitrophenyl chloroformate and 50 μl of pyridine(0.6 mmol) are dissolved in 2 ml of dichloromethane in a multistirrervessel and subsequently stirred at room temperature for 40 min. Asolution of 104 mg (0.904 mmol) ofC-(1-methylpyrrolidin-3-yl)methylamine and 230 μl ofdiisopropylethylamine in 1 ml of dichloromethane is subsequently added,and the reaction mixture is stirred at room temperature for 16 h. Forwork-up, the mixture is diluted with 20 ml of dichloromethane, the org.phase is washed with 10 ml of 1 N NaOH, dried over sodium sulfate andevaporated to dryness in a rotary evaporator. The purification iscarried out by chromatography (about 10 g of silica gel Si 60, 25-40 μm,gradient (dichloromethane/methanol):30 min 10-60% of MeOH/15 ml/min) Theproduct fractions are evaporated to dryness and crystallised fromdichloromethane/diethyl ether. Yield: 67 mg (24%) of (“A1”), m.p.105-107°; RT 4.45 min;

¹H NMR (250 MHz, DMSO-d₆) δ 8.453 (S, 1H), 7.859 (D, 2H), 7.550 (D, 2H),7.406 (S, 1H), 7.308 (D, 1H), 7.180 (T, 1H), 6.872 (D, 1H), 6.203 (T,1H), 4.976 (S, 2H), 4.331 (S, 2H), 3.053 (T, 2H), 2.493 (M, 2H), 2.422(M, 2H), 2.238 (M, 2H), 2.238 (S, 3H), 1.862 (M, 1H), 1.408 (M, 1H).

The following compounds are obtained analogously

M.p. [° C.]; No. Structure RT [min] “A2”

“A3”

¹H NMR (250 MHz, DMSO-d₆) δ 9.892 (S, 1H), 8.937 (S, 1H),7.862 (D, 2H),7.561 (D, 2H), 7.397 (S, 1H), 7.359 (D, 1H), 7.185 (T,1H), 6.877 (D,1H), 6.595 (T, 1H), 4.977 (S, 2H), 4.345 (S, 2H),3.174 (T, 2H), 3.101(M, 6H), 1.813 (M, 2H), 1.206 (T, 6H) 178-180;4.59 “A4”

¹H NMR (250 MHz, DMSO-d₆) δ 8.583 (S, 1H), 7.846 (D, 2H),7.542 (D, 2H),7.380 (S, 1H), 7.299 (D, 1H), 7.173 (T, 1H), 6.862 (D,1H), 6.124 (DD,1H), 4.969 (S, 2H), 4.741 (D, 1H), 4.321 (S, 2H),3.659 (M, 1H), 3.114(DD, 1H), 2.931 (DD, 1H), 1.043 (D, 3H) 143-144;4.96 “A5”

188-189;4.83 “A6”

143-144;4.96 “A12”

“A10”

152-154  “A11”

128-130 

EXAMPLE 2

The preparation ofN-{3-[5-(4-chlorophenyl)-2-oxo-6H-1,3,4-thiadiazin-3-ylmethyl]phenyl}-N′-(2-dimethylaminoethyl)oxalamide(“A7”) is carried out analogously to the following scheme

2.1

400 mg (1.205 mmol) of3-(3-aminobenzyl)-5-(4-chlorophenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one(from Example 1e) and 126 μl (1.567 mmol) of pyridine are dissolved in 5ml of dichloromethane in an 8 ml multistirrer vessel, and 147 μl (1.325mmol) of ethyl chloroformylformate are subsequently added at RT. Whenthe addition is complete, the mixture is stirred for a further 15 min.For work-up, the reaction mixture is diluted with 20 ml ofdichloromethane and subsequently washed with 10 ml of 1 N aqueous HCl,dried over Na₂SO₄ and evaporated to dryness in a rotary evaporator.

The residue is crystallised from methanol/diethyl ether. Yield 445 mg(85%) of ethylN-{3-[5-(4-chlorophenyl)-2-oxo-6H-1,3,4-thiadiazin-3-ylmethyl]phenyl}oxalaminate(“A9”), RT 5.68.

2.2

400 mg (0.926 mmol) of ethylN-{3-[5-(4-chlorophenyl)-2-oxo-6H-1,3,4-thiadiazin-3-ylmethyl]phenyl}oxalaminateare dissolved in 4 ml of methanol, and 47 mg (1.111 mmol) of LiOH×H₂Oare subsequently added. The reaction mixture is stirred at RT for 30min. For work-up, the reaction mixture is diluted with 30 ml ofdichloromethane and subsequently washed with 10 ml of 1 N aqueous HCl.During this operation, the product precipitates out in a separatingfunnel. The precipitate is filtered off with suction, triturated withdiethyl ether and dried at 50° C. in a drying cabinet. Yield 319 mg(85%) ofN-{3-[5-(4-chlorophenyl)-2-oxo-6H-1,3,4-thiadiazin-3-ylmethyl]phenyl}oxalamicacid (“A8”), RT 4.27.

2.3

120 mg (0.297 mmol) ofN-{3-[5-(4-chlorophenyl)-2-oxo-6H-1,3,4-thiadiazin-3-ylmethyl]phenyl}oxalamicacid, 27 mg (0.3 mmol) of N,N-dimethylethanediamine, 115 mg of EDCI (0.6mmol), 41 mg (0.3 mmol) of hydroxybenzotriazole and 61 mg (0.6 mmol) ofN-methylmorpholine are dissolved in 1 ml of dimethylformamide in an 8 mlmultistirrer vessel and stirred overnight at room temperature. Thereaction mixture is purified by RP-HPLC (acetonitrile/H₂O/0.1% of TFA:gradient 1-60% of B). Yield: 45 mg (32%) ofN-{3-[5-(4-chlorophenyl)-2-oxo-6H-1,3,4-thiadiazin-3-ylmethyl]-phenyl}-N′-(2-dimethylaminoethyl)oxalamide(trifluoroacetate) (“A7”).

EXAMPLE 3

Reaction of

with methylsulfonyl chloride under standard conditions gives compound“A13”

Compound “A14” is obtained analogously

Pharmacological Data Met Kinase Inhibition

TABLE 1 Compound No. IC₅₀ (enzyme) “A1” A “A2” A “A3” A “A4” A “A5” A“A9” A “A10” A “A12” A IC₅₀: 10 nM-1 μM = A 1 μM-10 μM = B >10 mM = C

The following examples relate to medicaments:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄ 2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which R¹ denotes H, A, Hal, OH, OA, SH, SA, SOA, SO₂A, NO₂, NH₂, NHA,NAA′, SO₂NH₂, SO₂NHA, SO₂NAA′, CONH₂, CONHA, CONAA′, NACOA′, NASO₂A′,COOH, COOA or CN, R² denotes H, A, Hal, SO₂NH₂, SO₂NHA, SO₂NAA′, CONH₂,CONHA, CONAA′, NACOA′, NASO₂A′, COOH, COOA or CN, R¹ and R² togetheralso denote methylenedioxy, B is absent, denotes NHCOCONH(CH₂)_(n)R³,NHCOCONA(CH₂)_(n)R³, NHCOCOO(CH₂)_(n)R³, OCONH(CH₂)_(n)R³,OCONA(CH₂)_(n)R³, NHCONH(CH₂)_(n)R³, NACONH(CH₂)_(n)R³, N(CH₂)_(n)R³,CONH(CH₂)_(n)R³, SO₂NH(CH₂)_(n)R³, SO₂NA(CH₂)_(n)R³, NHSO₂(CH₂)_(n)R³ orNASO₂(CH₂)_(n)R³, Q is absent or denotes alkylene having 1-4 C atoms, R³denotes R¹, Het or alkyl having 1-6 C atoms or cycloalkyl having 3-8 Catoms, each of which is unsubstituted or mono-, di-, tri- ortetrasubstituted by R⁴, R⁴ denotes A, Hal, OH, OA, SH, SA, SOA, SO₂A,NO₂, NH₂, NHA, NAA′, SO₂NH₂, SO₂NHA, SO₂NAA′, CONH₂, CONHA, CONAA′,NACOA′, NASO₂A′, COOH, COOA or CN, Het denotes a mono- or bicyclicsaturated heterocycle having 1 to 4 N, O and/or S atoms, which may beunsubstituted or mono-, di- or trisubstituted by R⁴, CHO, COA, ═S, ═NH,═NA and/or ═O (carbonyl oxygen), A, A′ each, independently of oneanother, denote unbranched or branched alkyl having 1-10 C atoms, inwhich 1-7H atoms may be replaced by F, Cl and/or Br, cycloalkyl having3-8 C atoms or cycloalkylalkylene having 4-10 C atoms, Hal denotes F,Cl, Br or I, n denotes 0, 1, 2 or 3, and pharmaceutically usablederivatives, solvates, salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 2. Compounds according toclaim 1 in which R¹ denotes Hal, OH or CN, and pharmaceutically usablederivatives, solvates, salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 3. Compounds according toclaim 1 in which R² denotes H or Hal, and pharmaceutically usablederivatives, solvates, salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 4. Compounds according toclaim 1 in which B denotes NHCOCONH(CH₂)_(n)R³, NHCOCOO(CH₂)_(n)R³,NHCONH(CH₂)_(n)R³ or NHSO₂(CH₂)_(n)R³, and pharmaceutically usablederivatives, solvates, salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 5. Compounds according toclaim 1 in which Q denotes CH₂, and pharmaceutically usable derivatives,solvates, salts, tautomers and stereoisomers thereof, including mixturesthereof in all ratios.
 6. Compounds according to claim 1 in which R³denotes H, Het or alkyl having 1-6 C atoms or cycloalkyl having 3-8 Catoms, each of which is unsubstituted or mono-, di-, tri- ortetrasubstituted by R⁴, and pharmaceutically usable derivatives,solvates, salts, tautomers and stereoisomers thereof, including mixturesthereof in all ratios.
 7. Compounds according to claim 1 in which R⁴denotes OH, NH₂, NHA or NAA′, and pharmaceutically usable derivatives,solvates, salts, tautomers and stereoisomers thereof, including mixturesthereof in all ratios.
 8. Compounds according to claim 1 in which A, A′each, independently of one another, denote unbranched or branched alkylhaving 1-6 C atoms, in which 1-5H atoms may be replaced by F and/orchlorine, and pharmaceutically usable derivatives, solvates, salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 9. Compounds according to claim 1 in which Het denotes amonocyclic saturated heterocycle having 1 to 2 N and/or O atoms, whichmay be unsubstituted or mono- or disubstituted by A, andpharmaceutically usable derivatives, solvates, salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 10.Compounds according to claim 1 in which R¹ denotes Hal, OH or CN, R²denotes H or Hal, B denotes NHCOCONH(CH₂)_(n)R³, NHCOCOO(CH₂)_(n)R³,NHCONH(CH₂)_(n)R³ or NHSO₂(CH₂)_(n)R³, Q denotes CH₂, R³ denotes H, Hetor alkyl having 1-6 C atoms or cycloalkyl having 3-8 C atoms, each ofwhich is unsubstituted or mono-, di-, tri- or tetrasubstituted by R⁴, R⁴denotes OH, NH₂, NHA or NAA′, A, A′ each, independently of one another,denote unbranched or branched alkyl having 1-6 C atoms, in which 1-5Hatoms may be replaced by F and/or chlorine, Het denotes a monocyclicsaturated heterocycle having 1 to 2 N and/or O atoms, which may beunsubstituted or mono- or disubstituted by A, Hal denotes F, Cl, Br orI, n denotes 0, 1, 2 or 3, and pharmaceutically usable derivatives,solvates, salts, tautomers and stereoisomers thereof, including mixturesthereof in all ratios.
 11. Compounds according to claim 1, selected fromthe group No. Structure “A1”

“A2”

“A3”

“A4”

“A5”

“A6”

“A7”

“A10”

“A11”

“A12”

“A13”

“A14”

and pharmaceutically usable derivatives, solvates, salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 12.Process for the preparation of compounds of the formula I according toclaim 1 and pharmaceutically usable derivatives, salts, solvates,tautomers and stereoisomers thereof, characterised in that a) a compoundof the formula Ia

in which B denotes NH₂, and R¹, R² and Q have the meanings indicated inclaim 1, is converted into a compound of the formula I in which Bdenotes NHCONH(CH₂)_(n)R³, by reacting a compound of the formula Ia witha coupling reagent selected from the group a) isoproylidenechloroformate, b) p-nitrophenyl chloroformate, c) diphosgene, d)triphosgene, and a compound of the formula IIH₂N(CH₂)_(n)R³  II in which n and R³ have the meanings indicated inclaim 1, or b) a compound of the formula Ia is acylated or sulfonylatedand/or a base or acid of the formula I is converted into one of itssalts.
 13. Medicaments comprising at least one compound of the formula Iaccording to claim 1 and/or pharmaceutically usable derivatives, salts,solvates, tautomers and stereoisomers thereof, including mixturesthereof in all ratios, and optionally excipients and/or adjuvants.
 14. Amethod for the treatment of diseases in which the inhibition, regulationand/or modulation of kinase signal transduction plays a role comprisingadministering a compound according to claim 1 or pharmaceutically usablederivatives, salts, solvates, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 15. Method according to claim14 for the treatment of diseases which are influenced by inhibition oftyrosine kinases.
 16. Method according to claim 14 for the treatment ofdiseases which are influenced by inhibition of Met kinase.
 17. Methodaccording to claim 15, where the disease to be treated is a solidtumour.
 18. Method according to claim 17, where the solid tumouroriginates from the group of tumours of the squamous epithelium, thebladder, the stomach, the kidneys, of head and neck, the oesophagus, thecervix, the thyroid, the intestine, the liver, the brain, the prostate,the urogenital tract, the lymphatic system, the stomach, the larynxand/or the lung.
 19. Method according to claim 17, where the solidtumour originates from the group monocytic leukaemia, lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas and breast carcinoma.
 20. Method according to claim 18,where the solid tumour originates from the group of lung adenocarcinoma,small-cell lung carcinomas, pancreatic cancer, glioblastomas, coloncarcinoma and breast carcinoma.
 21. Method according to claim 15, wherethe disease to be treated is a tumour of the blood and immune system.22. Method according to claim 21, where the tumour originates from thegroup of acute myeloid leukaemia, chronic myeloid leukaemia, acutelymphatic leukaemia and/or chronic lymphatic leukaemia.
 23. Medicamentscomprising at least one compound of the formula I according to claim 1,and/or pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios, and at least onefurther medicament active ingredient.
 24. Set (kit) consisting ofseparate packs of (a) an effective amount of a compound of the formula Iaccording to claim 1, and/or pharmaceutically usable derivatives,solvates, salts and stereoisomers thereof, including mixtures thereof inall ratios, and (b) an effective amount of a further medicament activeingredient.